Meeting Summary The 22nd annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday, 18 October 2013. The meeting was attended by 65 delegates from academia and industry; the life sciences; and chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Dr Karl Cable (GlaxoSmithKline, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Cholinergic basal forebrain neurons, important in memory formation, require nerve growth factor (NGF) for their continued maintenance and are vulnerable in Alzheimer's disease (AD). Application of NGF, through its interaction with tyrosine kinase receptor A (TrkA), has proven beneficial in both AD patients and animal models of AD. Levels of the NGF precursor protein proNGF are increased early in AD brain. Since proNGF has been shown capable of inducing apoptosis, via the p75NTR neurotrophin receptor and its co-receptor sortilin, it has been suggested that this may constitute an important factor in AD pathology. Objectives: Our aims were twofold; to produce small molecule agonists at TrkA and to use proNGF to generate a cell model of sporadic AD in which to test these. Small molecule TrkA binders were identified using in silico screening; and structural activity relationships determined using data collected from radioligand binding and agonist/antagonist assays in HEK cells over-expressing TrkA. Nuclear magnetic resonance (NMR) was used to confirm small molecule binding at TrkA. Non-cleavable proNGF (proNGF-nc) was added to PC12 cells, which were characterized for downstream responses including stimulation of intracellular signaling pathways (ERK and AKT), cell viability, neuritogenesis and caspase activation. We have identified a compound which displaces NGF with an IC50 of 3 ÂμM and can activate ERK in HEK-TrkA cells. It also binds to the isolated NGF-binding domain of TrkA (TrkAd5). PC12 cells express TrkA, p75NTR and sortilin and differentiate in response to NGF, as do cholinergic neurons. Contrary to expected outcomes, we demonstrate here that although less potent than NGF, proNGF-nc acted as a low affinity, but full agonist at TrkA. Moreover, at high concentrations proNGF-nc had equivalent efficacy to NGF. We show that blocking sortilin did not affect assay outcome. Similar results were obtained with differentiated PC12 cells. We have produced a potential lead compound towards generation of a small molecule therapeutic for AD. Our results also suggest that an increase in proNGF alone may not be sufficient to induce the AD pathological process, and that other concurrent changes may be necessary.

Pd and CO--ureally got me! The title reaction proceeds efficiently at 18 degrees C under CO (1 atm) with 5 % [Pd(OTs)(2)(MeCN)(2)] as precatalyst. Depending on the solvents used, either anthranilates or cyclic imides can be obtained in high yields (see picture, BQ = benzoquinone, Ts = 4-toluenesulfonyl).

A Pd-catalyzed intermolecular 1,2-carboamination route to indolines from N-aryl ureas and 1,3-dienes that proceeds under mild conditions in relatively nonacidic media, is presented. The in situ generation, or preformation, of a palladium tosylate emerges as a key parameter in gaining the requisite reactivity for the C-H insertion/carbopalladation/nucleophilic displacement process.

A selective three-component coupling, involving co-condensation of aldehyde pairs with substituted ureas under Lewis acid catalysis, provides rapid access to highly functionalised dihydropyrimidinones; sulfamides react analogously.